The anti-prion activity of Congo red. Putative mechanism.
PrPSc, an abnormal conformational isoform of the normal prion protein, PrPC, is the only known component of the prion, a proteinacious agent that causes fatal neurodegenerative disorders in humans and other animals. The hallmark properties of PrPSc are its insolubility in nondenaturing detergents and its resistance to digestion by proteases. Anions such as Congo red (CR) have been shown to reduce the accumulation of PrPSc in a neuroblastoma cell line permanently infected with prions as well as to delay disease onset in rodents when administrated prophylactically. The mechanism by which such anti-prion agents operate is unknown. We show here that in vitro incubation with CR renders native PrPSc resistant to denaturation by boiling SDS. This resulted from PrPSc conformation, since neither the properties of PrPC nor those of predenatured PrPSc were changed by the addition of CR. CR-PrPSc could only be denatured by the addition of acidic 3 M guanidine thiocyanate. Since in vitro conversion experiments have suggested that partial denaturation may be required for PrPSc to serve as template in the PrPC --> PrPSc conversion, we propose that CR inhibits prion propagation by overstabilizing the conformation of PrPSc molecules.
Caspi
S
S
Department of Neurology, Hadassah University Hospital, Jerusalem, 91120 Israel.
Halimi
M
M
Yanai
A
A
Sasson
S B
SB
Taraboulos
A
A
Gabizon
R
R
D000818:Animals; D001921:Brain / Q000648:ultrastructure; D003224:Congo Red / Q000494:pharmacology*; D006224:Cricetinae; D006146:Guanidines / Q000737:chemistry; D008647:Mesocricetus; D009447:Neuroblastoma / Q000648:ultrastructure; D011328:Prions / Q000737:chemistry / Q000187:drug effects*; D011489:Protein Denaturation; D012608:Scrapie; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013861:Thiocyanates / Q000737:chemistry; D014407:Tumor Cells, Cultured
D006146:Guanidines; D011328:Prions; D013861:Thiocyanates; D012967:Sodium Dodecyl Sulfate; D003224:Congo Red; C054436:guanidine thiocyanate